1. Field of the Invention
The subject matter presented herein relates to a method of determining risk of cancer and embryo health by evaluating CGG repeats on the FMR1 gene, and providing FMR1 related treatment.
2. Description of the Related Art
A dynamic triple-repeat sequence mutation in the X-linked gene, known as FMR1 (fragile X mental retardation 1), in its fully expanded form encompassing over 200 hypermethylated expansions of CGG, and expanding to the gene's promoter region, represents the full mutation for the so-called fragile X syndrome. Once the molecular biology of the syndrome was understood, it became apparent that between normal (or common) findings and full mutation, two additional stages of expansion exist, the so-called gray (or intermediate) zone and so-called premutations. There is consensus that premutations involve 55 to 200 repeats, and full mutations involve over 200 repeats. Whether the intermediate zone starts at 40 or 45 repeats has remained controversial, though, excluding American College of Obstetrics and Gynecology (ACOG) criteria, consensus is that the intermediate zone extends to 54 repeats.
Completely unaffected individuals most frequently demonstrate between 26 and 34 repeats with a median of approximately 30. Most laboratories, however, consider anything under 45 repeats a negative result. This may require reevaluation; because studies suggest that premature ovarian failure (POF) may be increased at intermediate size alleles of approximately 41 to 58 repeats. Experts, recently summarizing the state of the art after two federally funded consensus meetings, concluded that more data was needed to confirm this latter association. The ACOG considers a patient unaffected with ≦40 repeats, intermediate with 41-60, and a premutation between 61 and 200 repeats.
Carriers of premutations do not suffer from classical symptoms of fragile X, such as mental retardation. Their alleles, however, are in subsequent generations at significant risk of further expansion to the fully developed mutation. Carriers are, nevertheless, phenotypically affected: males with premutations are at increased risk for the so-called fragile X-associated tremor/ataxia syndrome (FXTAS), a progressive neurodegenerative disorder, whereas affected women have only a very low risk for FXTAS, but experience a high prevalence of premature ovarian failure (POF).
True POF represents an end stage of ovarian function. In many instances it is reached quickly and without preceding symptoms and/or laboratory abnormalities. In other cases, it may be preceded by lengthy periods of clinically symptomatic diminished ovarian reserve. When young women demonstrate symptoms of diminished ovarian reserve, such as age-specific elevated baseline follicle stimulating hormone (FSH) levels and/or ovarian resistance to stimulation with gonadotropins, an acronym of premature ovarian aging (POA) has been coined to differentiate these clinical circumstances from end-stage POF patients and women with ovarian senescence because of advanced age.
Such differentiation is important because, in contrast to POF, POA patients still demonstrate a fair chance of pregnancy with autologous oocytes up to b-FSH levels of approximately 40 mIU/mL, and therefore, represent a milder degree of ovarian dysfunction than POF. POA patients share the underlying pathophysiologies and etiologies of POF [Gleicher et al. Do etiologies of premature ovarian aging (POA) mimic those of premature ovarian failure (POF)? Human Reproduction 2009; 24:2395-400]. Thus, it appears that at least some POA patients will transition into POF, and that therefore, at least in these patients, POA may represent a continuum of impaired ovarian function.
Furthermore, both the FMR1 gene (in its various mutations/genotypes and sub-genotypes) and the so-called BRCA1/2 gene mutations, a known contributor to the causes of breast and ovarian cancer, affect ovarian reserve. FMR1 genotypes and subgenotypes also impact pregnancy chances in association with in vitro fertilization and define risk towards autoimmunity. Ovarian effects of BRCA gene mutations are, however, unclear. A better understanding of the interplay between BRCA1/2 mutations and the FMR1 gene, therefore, potentially may impact and improve screening for and therapeutic interventions in BRCA1/2-associated cancers. This may also result in improvement in determining a woman's pregnancy potential and accelerate appropriate clinical interventions and/or treatment for infertility related issues.